Summary:

New Medicines for Tuberculosis (NM4TB) aims to develop successfully new drugs
for the treatment of tuberculosis (TB) through an integrated approach
implemented by a team, which combines some of Europe’s leading academic TB
researchers with a major pharmaceutical company and three SMEs, all with a
strong commitment to discovering new anti-infective agents. NM4TB has a
comprehensive portfolio of potential and validated targets plus several novel
proprietary anti-TB agents in its drug development pipeline. Among the validated
targets are several enzymes involved in highly druggable areas such as cell wall
biogenesis, nucleic acid synthesis and central metabolic pathways for which
assays amenable to high-throughput screening are available. Intensive efforts
will focus on rapidly emerging targets that impact upon two, as yet, untouched
areas of the physiology of M. tuberculosis signal transduction pathways and
persistence.

Background:

Tuberculosis (TB) is one of the oldest diseases known to man and has infected
one third of the world’s population. As a result, someone dies from the disease
every 15 seconds and 30 million more people will lose their lives to TB in the
next decade. Although directly observed short-course chemotherapy is available
to treat the disease, this treatment is old, slow and inefficient by the current
standards of the pharmaceutical industry. Here the most innovative approaches
will be employed to identify and validate targets for new drugs, and implement
the screening and medicinal chemistry processes required to identify lead
compounds for the generation of candidate drugs.

Aims:

The aim of this project is to develop successfully new drugs for the
treatment of tuberculosis (TB) with the following desired properties:

high potency to reduce treatment duration

activity against persistent bacilli

inhibition of new target classes

activity against multidrug resistant TB

specificity forMycobacterium tuberculosis.

Expected results:

Development and implementation of novel enabling technologies required for drug development.

Target validation in well-established, ‘druggable’ areas such as the
central metabolism, cell wall and nucleic acid synthesis in addition to more
challenging, yet highly innovative, topics like the signal transduction and
persistence mechanisms.

Generation of structural information for as many targets as possible,
acting iteratively in the drug development process. Structures of targets with
drugs bound to rationally improve drug design.

Assay development and screening of deep chemical libraries encompassing
‘active’ to ‘hit’, ‘hit’ to ‘lead’ progression, and ‘lead’ optimisation
activities that give rise to candidate drugs.

Potential applications:

The proposed research will result in the development of new technologies and
assays for TB drug development, discovery of new classes of lead compounds for
fighting TB and lead optimisation and progression to candidate drug status.